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A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

Oakes, Samantha R; Gallego-Ortega, David; Stanford, Prudence M; Junankar, Simon; Au, Wendy Wing Yee; Kikhtyak, Zoya; von Korff, Anita; Sergio, Claudio M; Law, Andrew M K; Castillo, Lesley E; Allerdice, Stephanie L; Young, Adelaide I J; Piggin, Catherine; Whittle, Belinda; Bertram, Edward; Naylor, Matthew J; Roden, Daniel L; Donovan, Jesse; Korennykh, Alexei; Goodnow, Christopher C; O'Bryan, Moira K; Ormandy, Christopher J.
PLoS Genet; 13(11): e1007072, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29117179
We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation.
Selo DaSilva